Dysregulation of vitamin D3 synthesis leads to enhanced cholangiocarcinoma growth

• Published in: Digestive and liver disease 2013-04, Vol.45 (4), p.316-322
• Main Authors: Kennedy, Lindsey, Baker, Kimberly, Hodges, Kyle, Graf, Allyson, Venter, Julie, Hargrove, Laura, Harris, Rachel, Harnish, Evan, Meng, Fanyin, Francis, Heather
• Format: Article
• Language: English
• Subjects: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase - genetics; 25-Hydroxyvitamin D3 1-alpha-Hydroxylase - metabolism; Bile Duct Neoplasms - metabolism; Bile Ducts, Intrahepatic; Cell Line, Tumor; Cell Proliferation - drug effects; Cholangiocarcinoma; Cholangiocarcinoma - metabolism; Cholecalciferol - biosynthesis; Cholecalciferol - pharmacology; Degradation; Gastroenterology and Hepatology; Growth; Humans; Protein Transport - drug effects; Receptors, Calcitriol - genetics; Receptors, Calcitriol - metabolism; RNA, Messenger - metabolism; Steroid Hydroxylases - genetics; Steroid Hydroxylases - metabolism; Synthesis; Vitamin D3; Vitamin D3 24-Hydroxylase; Vitamins - biosynthesis; Vitamins - pharmacology
• ISSN: 1590-8658; 1878-3562
• DOI: 10.1016/j.dld.2012.12.012

Abstract Background Cholangiocarcinoma is a deadly biliary tumour with limited treatment strategies. Vitamin (1,25(OH)2 D) has anti-proliferative effects on several cancers. Vitamin D3 is synthesized by the enzyme, CYP27B1, and signals via the nuclear vitamin D3 receptor. The enzyme, CYP24A1, degrades vitamin D3. Aims (i) Measure the expression of CYP27B1, CYP24A1, and vitamin D3 receptor in human nonmalignant and cholangiocarcinoma lines and biopsy control or tumour samples; and (ii) evaluate the effects of vitamin D3 on vitamin D3 synthesis and cholangiocarcinoma growth. Methods In vitro studies were performed in malignant and nonmalignant cholangiocytes. Vitamin D3 receptor, CYP24 and CYP27 expression was measured in cell lines and biopsy samples. Cell lines were stimulated with vehicle or vitamin D3 from 30 min to 48 h. Cell viability was assessed by MTS assays and BrdU incorporation. Vitamin D3 receptor, CYP24A1 and CYP27B1 expression was measured in cholangiocarcinoma cells stimulated with vehicle or vitamin D3. Results In cholangiocarcinoma lines and biopsy samples, vitamin D3 receptor and CYP24A1 expression increased compared to controls, whereas CYP27B1 expression was decreased or unchanged. Vitamin D3 induced nuclear translocation of vitamin D3 receptor in cholangiocarcinoma and decreased cholangiocarcinoma growth. Conclusion Treatment with vitamin D3 decreased CYP24A1, whereas CYP27B1 expression increased. Modulation of vitamin D3 synthesis may be important in the management of cholangiocarcinoma.